ABSTRACT While it is well established that the stimulatory action of oxandrolone (OX) on muscle development is mediated by androgen receptors, various non-skeletal muscle-related actions of OX have also been demonstrated, including various effects on a) inflammatory mediator production and multiple-organ failure (MOF), b) angiogenesis/wound healing, and c) mitochondrial function/cellular bioenergetics. The exact molecular mode of OX's action on these processes in burn patients is incompletely understood, but, based on data in the literature and our own recent preliminary data, we hypothesize that it involves - at least in part - mechanisms other than the classical androgen receptor agonism mode of action. The goal of the current project is to delineate the pharmacological mode of selected non-skeletal-muscle-related actions of OX that are relevant for the pathogenesis of burn injury, using rodent models. In Aim 1 we will define the relative contribution of androgen receptor activation in the effects of OX on a) inflammatory mediator production and the pathogenesis of MOF, b) angiogenesis, and c) mitochondrial function (electron transport, ATP generation, and mitochondrial DNA integrity). In Aim 2 we will define the relative contribution of glucocorticoid receptor antagonism in the effects of OX on the same parameters; in Aim 3. we will define the relative contribution of the stimulation of H2S production by CSE on the same parameters and in Aim 4 we will determine the effect of OX therapy on various non-skeletal-muscle-related parameters in burn patients. Successfully completion of our Aims will clarify the complex modes of OX's therapeutic action on non-skeletal-muscle-related processes, and will lay the foundation for future studies designed to improve the experimental therapy of burns.